Primary lymphedema is a condition in which there is a deficiency of lymphatic drainage, leading to swelling, frequent recurrent cellulites, and disfigurement of the affected limb or lower torso, in the absence of vascular, cardiac, surgical, renal or hepatic causes for the edema. The PI has mapped three different forms of primary lymphedema inherited as autosomal dominants: primary congenital (PCL), onset with puberty (POL, the most common), and the rare lymphedema-distichiasis syndrome (LDS) in which there is hyperplasia of lymphatics, aplasia or hypoplasia of thoracic duct, and frequent cardiac malformations, in association with double row of eyelashes (distichiasis). The primary congenital lymphedema, mapped to 5q35.3, was recently shown by a group of investigators from Finland to be due in some families to missense mutations in the cytoplasmic tyrosine kinase domain of the vegfr3 gene. The specific aims of this proposal are two fold: 1) to investigate the genetic linkage relationship of 113 families to 3 sites of PCL, LDS and POL as well as other locations that may become available during the course of this study and, to determine the genetic contribution of each lymphedema locus to the overall presentation of this phenotype; and 2) to search for mutation in a number of POL (and/or PCL) candidate genes and eventually to identify, clone, isolate and characterize the putative lymphedema genes. Depending on these results, they may embark on another round of a genome-wide search at 5-cM intervals in order to identify the chromosomal location of as yet unknown other POL loci.